Cellular checkpoints are molecular pathways which are activated in response to DNA damage, such as DNA double-strand breaks (DSB). Pommier et al., 2005, Current Pharmaceutical Design 11:2855-2872. Modulation of these checkpoints can kill damaged cells via apoptosis or arrest cell cycle progression allowing for DNA repair prior to cellular reproduction, thus preventing or slowing tumor progression. Id. The ATM-Chk2 pathway, which is primarily activated by DSB, is thought to play a key role in apoptosis and cell cycle arrest. Id. Chk2 has emerged as an important multifunctional player in the DNA-damage response signalling pathway. Antoni et al., 2007, Nat. Rev. Can. 7(12):925-936. Without being limited by theory, the level of intrinsic DNA damage in a given tumor cell and the degree to which Chk2 functions are essential for maintenance of the transformed phenotype of the cell can guide the use of Chk2 inhibitors against the tumor. Id. For example, when there is high intrinsic DNA damage a Chk2 inhibitor could have potential for single-agent efficacy. Id. Whereas in tumors where activated Chk2 contributes directly to the malignant phenotype or to resistance to DNA-damaging agents, a combination of a Chk2 inhibitor with a DNA-damaging agent might be more useful. Id.
Inhibitors of Chk2 kinase are set forth in International Publication No. WO 2007/016338 A2, published Feb. 8, 2007. However, in view of the key role played by Chk2 in apoptosis and cell cycle arrest, there still remains a need for pharmaceutically useful inhibitors of Chk2.
RSK2 is a serine/threonine kinase involved in cell signaling which is activated by ERK and PDK1 (Kang et al., 2007, Cancer Cell. 12(3):201-14). Several investigators have found evidence for a role of RSK2 in malignant transformation (Cho et al., 2007, Cancer Res. (17):8104-12; David et al., 2005, J. Clin Invest. 115(3):664-72). Clark et al. have shown a role for RSK2 in regulation of prostate cancer growth and reported a novel inhibitor as a potential therapeutic lead (Clark et al., 2005, Cancer Res. 65(8):3108-16). Their work provides a strong rational for targeting RSK2 in prostate cancer. In addition, RSK2 appears to be essential for certain aspect of normal lymphocyte activation (Lin et al., 2008, Blood 111(2):525-33). Furthermore, in view of the role of this kinase in the HHV8 lifecycle, it is conceivable that an inhibitor could have an anti-viral effect (Kuang et al., 2008, J. Virol. 82(4):1838-50). RSK2 inhibitors have also been described by Cohen et al. (Cohen et al., 2007, Nat. Chem. Biol. 3(3): 156-60) and by Sapkota et al. (Sapkota et al., 2007, Biochem J. 401(1):29-38). However, there still remains a need for pharmaceutically useful inhibitors of RSK2.
Citation or identification of any reference in Section 3 of this application is not to be construed as an admission that the reference is prior art to the present application.